Malaria is a major infectious disease. Conservative estimates predict 2-300 million people are afflicted and over a million children die from the infection each year. The growing threat of drug resistant forms of malaria has created an urgent requirement for new drugs. Targeting unique features of the parasite not found in host cells provides one approach to new drug development. Plasmodium falciparum causes the most virulent form of human malaria. A striking feature of P.falciparum erythrocytic infection is targeting parasite proteins to the red cell. We have shown that targeting events are mediated by unique host-targeting signals on the proteins. Unlike organelles of yeast and mammalian cells, destinations in the red cell lie beyond the plasma membrane of the parasite. Moreover, the red cell has no endogenous transport structures or machinery. The long term aim of this proposal is to understand and characterize how the erythrocyte membrane is accessed by the intracellular parasite and the identification of erythrocyte chaperones and other erythrocyte targets that interact with critical parasite factors. The studies will contribute to our understanding of basic mechanisms of erythrocyte modification, biology of the parasite as well as open up new targets for anti- malarial therapy, and thereby contribute to human health. Molecular, genetic tools using transfection combined with bioinformatics, high resolution imaging techniques and biochemical subcellular fractionation assays will be used to express secretory constructs as trans genes and evaluate knockouts in infected erythrocytes. The consequence of trans gene expression and knock outs on variant antigen expression on the erythrocyte surface will be evaulated.These studies are important for understanding existing mechanisms of erythrocyte remodeling and malarial virulence.